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TB IntensiveSan Antonio, Texas

November 11‐14, 2014

Tuberculosis in Children Kim Smith, MD, MPHNovember 13, 2014

Kim Smith, MD, MPH has the following disclosures to make:

• No conflict of interests

• No relevant financial relationships with any commercial companies pertaining to this educational activity

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PEDIATRIC TUBERCULOSISKim Connelly Smith, MD, MPH

OUTLINE•Stages of tuberculosis•Differences of diseasein children and adults

•Diagnostic challengesof pediatric TB

•Treatment of TB in children•Clinical cases

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STAGES OF TUBERCULOSIS

Exposureto Contagious Adult with

Pulmonary Disease

Latent TB InfectionLTBI

Adult Active TB Disease

Child Active TB Disease

20-30%

5-10% Risk varies by age5-50%

Householdcontacts

0

10

20

30

40

50

60

0-12months

12-48months

4-11years

12-18years

HealthyAdults

Risk of Disease with no Treatmentby Age at Infection

Per

cen

t

Age at TB Infection

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RISK OF PROGRESSION TO TB DISEASE BY AGE

Age @ primary infectionBirth-12months

1-2 years

Risk of Disease

Disease 50%Pulmonary Dis 30-40%Miliary or TBM 10-20%

Disease 20-25%Pulmonary Dis 75%Miliary or TBM 2-5%

Marais BJ. Int J Tuberc Lung Dis 2004;8:392-402

TREATMENT OF TB IN CHILDREN

Stages of TB TST/IGRACXR/Lab Physical Symptoms Treatment

ExposureChild <4yrs (adult source)

Negative Normal None Window CPX 8-10 wksRepeat TST 8-10 wks after last contact

LTBI Positive Normal None INH x 9 months or Rif x 4-6 months

Disease 90% Positive

50% false negwith miliaryand TBM

AbnormalCXR, PE or labs

50% of children have symptoms

RIPE x 6-12 months, durationdepends on site

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Daycare Exposure

DAYCARE EXPOSURE

Index case, teacher assistant with AFB smear positive pulmonary disease and cough for 6 weeks

135 children < 4 years of age, plus adult staff members exposed

Smith, KC. Southern Medical Journal 93(9):877-880, 2000

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DAYCARE EXPOSURE MANAGEMENT

o Who is at risk?o Children and staff

o Who needs TST?o Everyone with significant contact with source case

o Who needs CXR?o All children less than 4 years of age even if TST negative o Any contacts with positive TST (> 5mm)

o Who needs treatment?o LTBI (positive TST >5mm and normal CXR) INH for 9 months or Rif x

4-6 monthso Exposed children less than 4 years of age (window prophylaxis)

o Follow up:o Skin test conversions: 4 adults and 3 childreno No TB disease

WINDOW PROPHYLAXIS FOR EXPOSURE

Household contact with contagious person Teen or adult with pulmonary TB disease Usually > 4 hours of contact

Initial TST negative Window period for TST conversion

(8-10 weeks) CXR and physical exam normal INH prophylaxis recommended:

For children <4 yrs of age Immunosuppressed patients May prevent progression to disease during

window period Repeat TST 8-10 wks after exposure May stop INH if 2nd TST negative <5mm in

immunocompetent patients

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PREVENTABLE CASE

PEDIATRIC TB CASE:MISSED OPPORTUNITY

15 mo old 10 days fussiness & decreased appetite 3 days inability to walk or sit up Lumbar puncture: CSF: 96 WBC (NL <7), 72% Lymphs,

198 Protein (NL <45), Glucose 8 Source case: mother of child Child’s diagnosis: TB Meningitis

Family history Mom with pulmonary TB diagnosed 5 mo earlier on

appropriate RIPE treatment Dad diagnosed with LTBI on INH Baby initial TST 0mm @ 10 months of age no CXR no treatment lost to follow up

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TB MENINGITIS

Youssef FG, et al. Diagn Microbiol Infect Dis 2006;55(4):275-8

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TB MENINGITISTREATMENT AND CLINICAL COURSE

9-12 months RIPE therapy Steroids for 1-2 month with 2-3 week taper

decreases CNS inflammation

Fever common for first month, symptoms may initially worsen followed by gradual improvement

Possible complications Seizures Hydrocephalus CNS tuberculoma, stroke, mental disabilities, CP Mortality high (>90%) if not diagnosed and treated

*Feigin & Cherry, Text of Pedi ID

TTimetable of Tuberculosis

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DIFFERENCES INADULT AND PEDIATRIC TB

REACTIVATION DISEASE

Occurs years after primary infection

Typical of adult disease Occasionally seen in

teens Often cavitary disease High numbers of

organisms (AFB +) Usually symptomatic

and contagious

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PRIMARY TB DISEASE

Typical of childhood TBUsually not cavitary

Classic x-ray: Hilar lymphadenopathy +/-

infiltrates or Miliary pattern

Low numbers of organisms AFB smears negative (95%) Cultures negative in 60% of

cases

Most children <12 yrs not contagious

Often asymptomatic (50%)

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RADIOGRAPHIC FINDINGS INPEDIATRIC TB DISEASE

Hilar and interthoraciclymphadenopathy

Miliary pattern

Basilar enhancement on brain imaging

Apical cavitary lesions in adults and teens

Lobar pneumonia

Pleural effusion in adults and teens

Typical of TB Not specific but common

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TB DISEASE

Pulmonary

Extrapulm

15%85%

Pulmonary

Extrapulmonary

25%75%

Adult TB Disease Pediatric TB Disease

Lymphatic25%

Pleural23%GU

16%

Meningeal4%

Bone/Joint10%

Miliary9%

Other13%

Adult Extrapulmonary TB Disease (15%)

Lymphatic

Pleural

GU

Meningeal

Bone/Joint

Miliary

Other

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Lymphatic65%

Meningeal14%

Pleural6%

Miliary 5%

Other5%

Bone/Joint5%

Extrapulmonary TB Disease in Children (25%)

Lymphatic

Meningeal

Pleural

Miliary

Other

Bone/Joint

COMMON SYMPTOMS OF TB DISEASE IN CHILDREN

(NONSPECIFIC)

Cough and/or respiratory distressPulmonary findings on examinationLymphadenopathy or lymphadenitisS/Sx of meningitis including seizuresPersistent fever (FUO)Weight loss or failure to thriveUnlike adults, up to 50% of children with

TB disease have no symptoms

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DIAGNOSIS OF TB IN CHILDREN

Gold Standard –Positive TB Culture

OR, Clinical Diagnosis:Abnormal CXR, laboratory,

or physical examination consistent with TB AND1 or more of the following: Positive tuberculin skin test or

IGRA Contagious adult source case

identified Clinical course consistent with

TB disease, or Improvement on TB therapy

DIAGNOSTIC TRIADPEDI TB DISEASE

1. Positive TST

2. Abnormal CXR

3. Infectious source case

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GASTRIC ASPIRATES

Inpatient procedure

Overnight fasting

Lavage with normal saline

Collected in morning x 3 days

Inpatient costs substantial

AFB smear yield: <5%

Sensitivity of culture 20-50%

Future: possible use of NAAT’s in children

INDUCED SPUTUM

Outpatient procedure 2-3h fasting period Pretreatment:

Nebulized bronchodilator and hypertonic saline

Chest physiotherapy (CPT) Nasopharynx suctioned One specimen sufficient Minimal costs Yield equivalent to GA’s

Lancet. 2005;365:130

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TB CULTURES FROM CHILDREN

Bronchoalveolar lavage (BAL) Single specimen with similar yield to 3 GA’s Sensitivity 40% (20-50% range)

Lymph nodes Biopsy or FNA for path and culture Sensitivity 30-70% on culture

CSF in TB meningitis High volume (> 6 ml) improves yield Sensitivity 20% average (12-50% range)

Nucleic acid amplification tests (NAAT) in children Data limited especially from U.S. Sensitivity estimated at 60-85%

Bottom line Negative test does not rule out

disease

TUBERCULIN SKIN TEST AND

INTERFERON GAMA RELEASE ASSAYS (IGRA)

Sensitivity 90% 50% in disseminated TB

Specificity 85% Lower in BCG

vaccinated

Cross reacts with BCG vaccine Many NTM

Sensitivity 75-90% Children 90% Lower in developing

countries and children <5 years of age (50-90%)

Specificity 90-99%

Cross reactions None with BCG Only 3 NTM

M. kansasii, M. marinum, M. szulgai

Tuberculin Skin Test IGRA (QFT or TSPOT)

Both TST and IGRA tests may be helpful in difficult cases

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Machingaidze et al. PIDJ 2011; 30: epub

Quantiferon and TST in Children

IGRA SENSITIVITY IN CHILDREN < 5 YRSOF AGE INSUFFICIENT TO REPLACE TST

Test Sensitivity <5 years (CI)

Sensitivity >5 years (CI)

Specificity

TST 90% (79-100) 98% (93-100) NA, ref standard

QFT-G-IT 73% (58-89) 93% (84-100) 93% (88-99)

T-SPOT.TB 63% (46-80) 83% (75-90) 92% (87-99)

Chiappini E. PIDJ. 2014:33:1291-1293.338 children total, 210 not infected, 58 LTBI, 42 probable TB disease by clinical criteria, 28 culture confirmed disease

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TB  Risk Questionnaire 

positive?

Age < 5 years?

BCG Vaccinated?

Screening Complete

TST Preferred

IGRA Preferred

TST or IGRA Acceptable

No

No

Yes

No

Yes

Yes

Algorithm for TB Testing in Children

Consider•Cost•Confidence in test •Ability to return

WHAT TO DO WITH DISCORDANT IGRA AND TST RESULTS?

For healthy patients (5 yrs or older) without high risk for disease Choose the more specific test (IGRA)

If the patient is sick, under 5 years of age or at high risk of disease Consider either test positive for highest sensitivity

Indeterminate results means the control failed Repeat the test

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EXPECTED CLINICAL COURSEFOR TB DISEASE IN CHILDREN

Pulmonary CXR takes months to improve

Hilar lymphadenopathy May take a year or more to regress on x-ray

Cervical lymphadenitis Gets worse before improvement over months-years

Meningitis Inflammation and symptoms sometime increase

initially with treatment

MONITORING CHILDRENON TB TREATMENT

Risk of drug toxicity very low Monitor clinical signs

regular clinical visits (4-6 wks) patient education

Routine blood work not necessary unless symptoms risk factors for toxicity

Monitor and reinforce adherenceWhen to follow up CXR’s for pulmonary TB

Beginning and end of therapy Anytime if clinical change

Completion of therapy certificate

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TB MEDICATIONS IN KIDS

Hepatotoxicity rare INH liquid vs tabletsMedication refusal in children Crush tablets, medication sandwich

Vitamin B6 Not needed for all kids Important for

Breastfed infants Teens and/or picky eaters Patients with symptoms of peripheral neuropathy

Going back to school Children <12 yrs of age are not contagious

CENTRAL NERVOUS SYSTEMTB DRUG PENETRATION

Isoniazid Rifampin PZA Ethambutol Ethionamide Aminoglycosides Fluoroquinolones

Good Inflamed meninges only Good Inflamed meninges only Good Inflamed meninges only Good except Cipro poor

Drug CNS Penetration

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ETHAMBUTOL IN CHILDREN

Risk of optic neuritis: Visual acuity Color perception Dose related Usually reversible Risk around 1-3% in adults Risk in children about the same

EMB safe in children with monitoring Monitor vision on treatment Infants – visual evoked potentials (VEP)

Table 2. Studies that have specifically sought optical toxicity in children treated with Ethambutol

Reference Patients (n) Age range Method of evaluation Length of follow up Number with(months) toxicity

2425

Fox*262728

4736

4530276

3-13 years4 months to 16 years1-15 years4-5 years5-15 years9-16 years

Visual evoked responsesAcuity/field/colour

Acuity/field/colourAcuity/field/colourAcuity/field/colourComputerized visual fieldexamination

15-1824-48

9-18612-369

00

0000

*Fox W, unpublished data quoted in Tubercle 1986; 67:27.

SM Graham. Arch Dis child 1998; 79:274-278.

Ethambutol in Children

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*B Hampel. Pediatr Inf Dis J, 1997;16:127-9.

FLUOROQUINOLONES IN CHILDREN

Initial clinical trials in children not done Some children have been treated without

problems: CF, chronic UTI, shigellosis and TB

Most consider safe in children: Some case series and RCT with good results Germany study: 2030 patients treated, 31 (1.5%)

with self resolving arthralgia*

Not indicated for routine infections in children Consider risks and benefits Monitor clinically for joint and tendon

problems

Comparison of Side Effects with Ciprofloxacin vs Ceftazidime/Tobramycin in Children

No. of Patients

Event CiprofloxacinCeftazidime/TobramycinN = 62 (%)N = 67 (%)

P

Any 52 (78) 43 (69) 0.288Abnormal liver function tests 17 (25) 13 (21) 0.554Injection 16 (24) 5 (8) 0.015Injection site pain 13 (19) 7 (11) 0.203Rash 10 (15) 5 (8) 0.225Phlebitis 7 (10) 1 (2) 0.063Vomiting 11(16) 4 (6) 0.078Central nervous system, any 1 (1) 6 (10) 0.055Respiratory, any 7 (10) 3 (5) 0.328Musculoskeletal, any 15 (22) 13 (21) 0.845

Joint Disorder 8 (12) 10 (16) 0.493Arthralgia 7 (10) 7 (11) 0.878Arthritis 1 (1) 0 (0) 1.0Leg cramps 0 (0) 1 (2) 0.481Myalgia 1 (1) 0 (0) 1.000

DA Church. Pediatr Infec Dis J 1997 Jan; 16 (1): 97-105

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PEDIATRIC TB CASES

LYMPHADENOPATHY

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CLINICAL CASE

CERVICAL LYMPHADENOPATHY

8 yr old with cervical lymphadenopathy

History: LAN for 3 months PMHx: HealthyBCG vaccine at birth

TB skin test 10 mmPhysical Exam:

3 cm anterior cervical LAN 1.5 cm supraclavicular

lymphadenopathy CXR:

Hilar LAN, no infiltratesIs this TB disease?What else could it be?

HILAR & CERVICALLYMPHADENOPATHY

Differential Dx Tuberculosis Non TB mycobacteria (NTM) Lymphoma/Leukemia HIV Other causes

Diagnostic tests Biopsy (FNA or surgical for

culture and path) Interferon blood test for TB

infection

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RESULTS

Fine needle aspirate of node: Pathology: lymphoma, no TB by culture or microscopy

Interferon Blood test for TB Positive Diagnostic for latent TB infection or disease

Diagnoses: LTBI

AND Hodgkin’s Lymphoma

Treatment: Chemotherapy for lymphoma AND INH daily for 9 months for LTBI

consider prolonged treatment during immunosuppresion

Skin Test in Foreign Born

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SKIN TEST IN FOREIGN BORN

6 year old with positive TST for school entry Born in Asia BCG documented on vaccination records at birth

and BCG scar present TST measures 12mm

CXR NORMAL

How do you interpret the 12 mm skin test?

Is this BCG effect or LTBI?

Are there any other tests that may help?

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TB IN NEWBORN NURSERY

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NEW MOTHER WITH POSITIVE TST

Newborn infant in hospital nursery Mother with 15 mm TST CXR: calcified granuloma no active disease Not on treatment

What is mother’s diagnosis? Do mother or baby need isolation? May baby breast feed and room with mother?

Maternal TB disease or LTBI during pregnancy

Is mother contagious?

Exposure to contagious household TB contact:• Window prophylaxis

for baby• Multivitamin for baby• Okay to breastfeed

If no exposure to contagious household TB contacts:• No treatment for

baby• Okay to breastfeed

No Yes

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PREVENTION OF TB DISEASEIN CHILDREN

Contact Investigation

INH Window Prophylaxis

Treatment of LTBI

RESOURCES

HNTC Pedi TB Toolbox Guidelines and clinical tools Reference materials Patient education materials

TB Testing in Children Brochure

Pediatric Radiology for Clinicians

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TREATMENT OF TUBERCULOSIS IN CHILDRENStages of TB Skin Test or

IGRACXR SXs Treatment

Exposure Child < 4 years of age Household contact with adult with active pulmonary disease

TST Negative Normal None Meds: INH window prophylaxisDuration: 8-10 weeksRepeat skin test: 8-10 wks after expif positive > 5mm, see LTBI

Latent TB infection (LTBI) Positive Normal None Meds: INHDuration: INH 9 mo or RIF 4-6 mo

DiseasePulmonary and extrapulmonary(except disseminated disease and meningitis, see below)

90% positive Abnormal +/- Meds: INH, RIF, PZA(consider EMB or an aminoglycoside) Duration: 6 mo total, Stop PZA after 2 mo, continue INH & RIF for susceptible disease

DiseaseDisseminated including miliary, bone/joint and multi-site disease

TST may be negative early in disseminated TB, most positive by end of treatment

+/- Yes Meds: INH, RIF, PZA and EMB or an aminoglycosideDuration: 9-12 mo total Stop PZA and EMB or aminoglycoside after 2 mo for susceptible disease

DiseaseMeningitis

Often negative early in meningitis and miliary disease90% positive by end of tx

+/- Yes Meds: INH, RIF, PZA and Ethionamide, or an aminoglycosideor EMB daily for 2 mo, then INH and RIF for 7-10 moDuration: 9-12 mo total for drug susceptible diseaseSteroids recommended for first 1-2 mo for meningitis